The goal of the K01 candidate is to establish an independent research program on neurodegenerative dementias, with the main focus of improving public health through the advancement of multi-modal imaging capabilities to diagnose Alzheimer's disease (AD) early on and monitor its progression. Because self- appraisals guide much of human behavior, inaccurate judgments shown by many AD patients (i.e., impaired self-awareness or anosognosia) can yield serious consequences, and poses a major problem in the diagnosis, treatment and care of the patient. Despite the impact of anosognosia on patients and their caregivers, our knowledge of its clinical and neurological correlates as well as prognostic value is poorly understood. The research proposed herein specifically aims to investigate the neural underpinnings of memory self-awareness and the progressive dysfunction of these systems that underlie the loss of self-awareness with AD progression. Specifically, we propose to probe the mechanistic underpinnings of self-awareness of memory utilizing an innovative and novel combination of multi-modal imaging techniques. Our preliminary data, using functional connectivity analysis (as assessed with resting state fMRI, fcMRI) provides further proof that the posterior cingulate and medial prefrontal cortex, two major hubs in the default mode network (DMN), are crucial for accurate memory self-appraisal. Here, we propose to combine fcMRI with a novel fMRI task that investigates the critical neuroanatomy subserving accurate assessment of memory performance to study how this relates to memory self-awareness. Additionally, we plan to use transcranial magnetic stimulation (TMS) to demonstrate that the DMN is causally related to self-assessment of memory performance in our fMRI task. Whether perceived changes in memory in older adults parallel changes in brain pathology indicative of AD is uncertain. The candidate's preliminary work suggests that increased A? deposition (a major histopathological finding in AD) in healthy older adults modifies the association between memory self-appraisal and functional connectivity within the DMN, such that increased subjective memory complaints were related to decreased connectivity between the medial prefrontal cortex and posterior cingulate. To investigate this further, we will use data across the clinical stages of AD (including mild cognitive impairment and mild AD patients) to determine whether impaired memory self-awareness coincides with functional disconnection and increased A? pathology in core regions of the DMN. Furthermore, using longitudinal data of older adults and patients across the clinical stages of AD, we will investigat whether pathophysiological changes in the DMN portend loss in memory self- awareness and anosognosia at follow-up (4 years). The proposed research will leverage a rich multi-modality dataset available from a NIA-funded cohort (Harvard Aging Brain Study) and provides a unique avenue of investigation for the candidate. The findings are expected to have important clinical implications, as improved understanding of anosognosia may lead to interventions that would lessen its impact on wellbeing.